1. Technical Field
The present disclosure relates to a manufacturing method of a microstructure such as a microneedle using an air blowing method. More particularly, the present disclosure relates to a manufacturing method of a microstructure such as a microneedle using a blowing method, which improves a process of forming a bottom layer that is a basis of a microstructure formation in a conventional manufacturing method of a microstructure.
2. Description of the Related Art
Despite the development of numerous drugs, bioactive substances and the like for treating diseases, problems involving the passage of biological barriers (e.g., skin, oral mucosa, and brain-blood vessel barrier) and the efficiency of drug delivery still remain to be improved in view of delivering the drugs into a human body.
Generally, drugs and bioactive substances are orally administered in a dosage form of a tablet or capsule, but numerous drugs cannot be effectively delivered through only the above administration manner because they are digested or absorbed in the gastrointestinal tract or lost due to hepatic mechanisms. Moreover, some drugs cannot be efficiently diffused when passing through the intestinal mucosa. Also, patient compliance is problematic (for example, critical patients who need to take drugs at predetermined intervals or cannot take drugs).
Another general technique for drug delivery is to use conventional needles. While this technique is more effective than oral administration, it causes pain at the injection sites, local damage to skin, bleeding, or infections at the injection sites.
For addressing the above described problems of oral administration and a subcutaneous injection, a transdermal administration method through patches is used. While the transdermal administration using patches has advantages in that side effects are small, patient compliance is high, and maintaining blood concentration of drugs constantly is easy, this has disadvantages in that drugs permeable to skin are limited and the efficiency of drug delivery is low.
To address the above described problems, a variety of microstructures including a microneedle have been developed. Recently developed microneedles have been mainly used for in vivo delivery of drugs, blood collecting, detection of in vivo analytes, and the like.
Unlike the existing needles, the microneedle has features of painless skin penetration and causing no wounds, and a diameter of a top portion for the minimum sharpness is important in the painless skin penetration. In addition, the microneedle is required to have a sufficient physical hardness because it needs to pass through the stratum corneum of 10 to 20 μm, which is the thickest barrier in the skin. The microneedle needs to also have an appropriate length in order to improve the efficiency of drug delivery by reaching capillary vessels. Conventionally, since the proposal of an in-plane type microneedle (“Silicon-processed Microneedles,” Journal of Microelectrochemical Systems 8, 1999), various types of microneedles have been developed. According to a method of manufacturing an out-of-plane type solid microneedle using an etching technique (disclosed in U.S. Patent Publication No. 2002138049, entitled of “Microneedle Devices and Methods of Manufacture and Use Thereof”), a solid silicon microneedle is manufactured to have a diameter of 50 to 100 μm and a length of 500 μm. However, the microneedle could not realize the painless skin penetration, and had difficulty in delivery of drugs and cosmetic ingredients to a target region.
Meanwhile, Prausnitz (Georgia Institute of Technology, U.S.A.) has suggested a method of manufacturing a biodegradable polymer microneedle by producing a mold by performing etching or photolithography on glass (Biodegradable Polymer Microneedles: Fabrication, Mechanics and Transdermal Medicine Delivery, Journal of Controlled Release 104, 2005, 5166). Also, in 2006, a method of manufacturing a biodegradable solid microneedle by loading a material manufactured in a capsule type onto an end part of a mold manufactured by photolithography was suggested (Polymer Microneedles for Controlled-Release Medicine Delivery, Pharmaceutical Research 23, 2006, 1008). According to the above described method, it is easy to load a drug which can be manufactured in a capsule type, but when a large amount of such a drug is loaded, the microneedle is degraded in hardness, and thus there is a limitation to application to a drug that needs to be administered in a large dose.
In 2005, an absorbable microneedle was manufactured by Nano Device and Systems Inc. (Japanese Patent Publication No. 2005154321; and “Sugar Micro Needles as Transdermic Drug Delivery System,” Biomedical Microdevices 7, 2005, 185). Such an absorbable microneedle is used in drug delivery or cosmetics without removing the microneedle inserted intradermally. According to the above described method, a composition prepared by mixing maltose with a drug is applied to a mold and then solidified to thereby manufacture a microneedle. The Japanese patent discloses a manufacturing of an absorbable microneedle for transdermal absorption of drugs, but skin penetration of the absorbable microneedle is accompanied by pain.
In addition, due to a technical limitation to the manufacture of a mold, it is very difficult to manufacture a microneedle having a top portion of a suitable diameter causing no pain and a length required for effective drug delivery, that is, a length equal to or greater than 1 mm.
A biodegradable microneedle suggested by Prausnitz (Georgia Institute of Technology, U.S.A.) in 2008 was manufactured using a polydimethylsiloxane (PDMS) mold and a material prepared by mixing polyvinylpyrrolidone (PVP) with methacrylic acid (MAA) (Minimally Invasive Protein Delivery with Rapidly Dissolving Polymer Microneedles, Advanced Materials 2008, 1). Also, a microneedle was manufactured by injecting carboxymethylcellulose into a pyramid-structure mold (Dissolving Microneedles for Transdermal Medicine Delivery, Biomaterials 2007, 1). However, the method using a mold has a limitation in that a new mold and frame should be manufactured through a complicated process so as to adjust a diameter and a length of the microneedle, and further has a disadvantage in that a process of injecting a material into a mold to manufacture the micro needle is a complicated and time consuming process.
In 2008, an apparatus and a method for manufacturing a skin needle using a pin structure were presented through U.S. Patent registered by Mukai et al. of Japan (U.S. Pat. No. 20080157421A1). This method employs a technique of pulling a viscous material using a tensile force thereof with a pin by heating the viscous material at a base of a substrate. Owing to the technique of pulling a material, which is melted by heat or has viscosity, with a pin structure, a limitation of this method still remained in an increase of a manufacture cost due to a process for newly manufacturing a pin structure depending on a desired pattern, and difficulty in loading various thermosensitive biopharmaceuticals (a hormone, a vaccine, other protein drug, and the like) due to the heating process.
Meanwhile, the skin is composed of a stratum corneum (<20 μm), an epidermis (<100 μm), and a dermis (300 to 2,500 μm), which are sequentially stacked from an outer layer of the skin. Therefore, in order to deliver drugs and bioactive substances to a specific skin layer with no pain, a microneedle will be manufactured to have a diameter equal to or greater than approximately 30 μm at a top portion, an effective length of 200 to 2,000 μm, and a sufficient hardness to skin penetration such that the drugs and skin care ingredients may be effectively delivered. In addition, in order to deliver drugs, bioactive substances and the like through a biodegradable solid microneedle, it could exclude a process, which may destroy activities of the drugs and the bioactive substances, including a high heat treatment, an organic solvent treatment and the like from the microneedle manufacturing process.
A conventional solid microneedle is limited to be manufactured with a material including a silicon, polymers, a metal, a glass and the like due to a limitation of the manufacturing method, and it has disadvantages in that drug degeneration, insufficient hardness, a loss of a drug, and the like occur according to a complicated and highly time consuming manufacturing process due to a manufacturing method using a molding technique. Consequently, there are ongoing demands for a method of manufacturing a microneedle, wherein the method is capable of implementing a sufficient hardness with no specific limitation to a material while having a thin diameter to realize skin penetration with no pain and a sufficient length to deeply penetrate into a skin, and minimizing a loss of a drug.
To address the problems as described above, the present inventor disclosed a totally new method for manufacturing a microstructure in Korean Patent Application No. 10-2010-0130169 (Title of Invention: Method for Manufacturing a Microstructure). The method for manufacturing a microstructure is schematically shown in FIG. 1. This will be described in brief as follows.
Firstly, in a forming of a bottom layer, a first viscous material 11 is applied to a first substrate 10 and then is dried (coagulated) to form a bottom layer. At this point, an air blowing may be performed so as to facilitate the coagulation. Here, the first substrate 10 is formed in a plane shape, and any material may be applicable to the first substrate 10. For example, the first substrate 10 may be manufactured with a material including a polymer, an organic chemical material, a metal, a ceramic, a semiconductor and the like. However, when a microneedle is manufactured for medical and pharmaceutical purposes, it may be preferable to manufacture the first substrate 10 with a material that is not harmful to a human body. After Operations (Operations (a) and (b) of FIG. 1) of applying the first viscous material 11 to the first substrate 10 and coagulating it to form the bottom layer, a second viscous material 12 is spotted to form a base structure layer. As similar to the forming of the bottom layer, an air blowing may be performed to coagulate and form the base structure layer. The base structure layer is a layer that is formed by being spotted on the bottom layer for the purpose of precisely adjusting an amount of a pharmaceutical ingredient, which is injected into a human body, when another viscous material being spotted on the base structure layer, that is, a third viscous material 13 is a functional material such as a medicine and the like, and such a base structure layer may be omitted depending on a circumstance (Operations (c) and (d) of FIG. 1). After the forming of the base structure layer, the third viscous material 13, which is a material of a microneedle penetrating into the human body, is spotted on the base structure layer (Operation (e) of FIG. 1). When the base structure layer is omitted, the third viscous material 13 may be spotted on the bottom layer.
Under such a circumstance, as shown in Operation (f) of FIG. 1, a second substrate 20, on which a bottom layer is formed by the same manner as described above, is downwardly moved in a state of directing the bottom layer to face the third viscous material 13 to come into contact therewith, and thereafter, as shown in Operations (g) and (h) of FIG. 1, it is upwardly moved to stretch the third viscous material 13. The stretched third viscous material 13 is coagulated in an air blowing manner and the like. Afterward, as shown in Operation (i) of FIG. 1, the stretched third viscous material 13 is cut in a state in which the third viscous material 13 was completely coagulated so that a microneedle structure is generated.
According to the conventional microstructure manufacturing method by the present inventor as described above, it can not only realize a sufficient hardness, but reduce a loss of a functional material so that most of the above described problems may be solved.
However, in the conventional microstructure manufacturing method by the present inventor as described above, the damage to the bottom layer or the microneedle structure occurs in the course of separating the bottom layer from the first and second substrates 10 and 20 so as to attach the microneedle structure, which is formed on the bottom layer, to a patch type product that is able to adhere to the skin.
Also, there is a disadvantage in which a thickness of the bottom layer is not maintained uniformly. When a thickness of the bottom layer is thicker than an intended thickness and a stretching of the same length as described above is performed, upper and lower lengths of the microneedle, which is made of the third viscous material 13 that is spotted on the bottom layer and is stretched to be formed, may be shorter than intended upper and lower lengths, and in this case an upper end part of the microneedle does not arrive at the stratum corneum so that the efficiency of drug delivery may be reduced. In addition, at the same time, a cross-sectional diameter of the upper end part of the microneedle may be increased (a phenomenon occurs due to shortened lengths, which were stretched upwardly and downwardly, despite of spotting the same volume of a viscous material), and thus pain may be induced when the microneedle is adhered to the skin. Contrarily, when the thickness of the bottom layer is thinner than the intended thickness and a stretching of the same length as described above is performed, the cross-sectional diameter of the microneedle may be smaller than an intended cross-sectional diameter. Therefore, the upper and lower lengths may be longer than the intended upper and lower lengths to cause a decrease of the physical hardness so that a diameter and hardness, which are suitable for the skin penetration, may not be provided and thus the efficiency of drug delivery may be reduced.
Further, the thickness of the bottom layer should be uniformly maintained. When the thickness of the bottom layer is not formed uniformly, the cross-sectional diameter of the microneedle and the upper and lower lengths thereof may be varied depending on a position of the microneedle so that the physical hardness and the upper and lower lengths are not uniform as described above, and as a result, the pain may be induced or the efficiency of drug delivery may be reduced when a user adheres the microneedle to the skin.
However, according to the microstructure manufacturing method by the present inventor as described above, the bottom layer is formed after the first viscous material 11 is applied on the first substrate 10 and then is coagulated, and shortly afterward, the second and third viscous materials 12 and 13 are spotted on the bottom layer so that a next process is immediately performed without inspecting whether or not a thickness of the bottom layer is formed with an intended thickness. Consequently, there is a problem in that a defective determination can be carried out unnecessarily after the forming of the microneedle structure on the bottom layer because the defective determination cannot be carried out immediately when a thickness of the bottom layer deviates from the intended thickness.
Another additional problem is that a process time is longer. This problem also relates to a forming of the bottom layer. Because one hour at minimum to more than several hours may be typically required to dry the viscous material to form a layer, there is a problem in that productivity is decreased due to a process of applying the first viscous material 11 so as to form the bottom layer, and a consecutive coagulating process by an air blowing.